The big-serving American battled to the 7-6 (7-4) 7-6 (9-7) win in Auckland on Saturday, adding to the title he won there in 2010.
The third seed served 23 aces but failed to capitalise on any of his 10 break points as he made life difficult for himself.
Isner's win gave him his first title since July in what was Lu's first career ATP World Tour final.
Yen- Hsun Lu reacts to a point in the singles final against John Isner. Photo by Anthony Au-Yeung/Getty Images
Lu wasted a rare break point in the second game of the match, Isner squandered two in the third and another in the fifth as they headed for a tie-break.
And with his powerful serve, Isner was always going to be hard to stop once he eased out to a 3-0 lead.
Isner had opportunities to break in the second and sixth games of the second set but Lu fought hard.
And the Taiwanese right-hander led 3-0 in the tie-break before Isner fought back to 5-5 and then converted his third championship point at the ATP 250 event.
John Isner serves in the singles final against Yen- Hsun Lu. Photo by Anthony Au-Yeung/Getty Images